CHAPTER 1: INTRODUCTION Heterogeneity of major depressive disorder Depression, or major depressive disorder, is a mental disorder that dramatically affects a person's health and life. It is characterized by persistent low mood, inability to feel pleasure in previously enjoyable activities, feeling of low-esteem, fatigue, sleep disturbances, appetite changes, pain without a clear cause, and thoughts of suicide. It has become the leading cause of disability worldwide with over 300 million people affected. The prevalence of major depressive disorder increased by 18% from 2005 to 2015 (World Health Organization, 2017). Depression is also a chronic disease, as half of a people who experienced a single episode are likely to have recurrent episodes with higher frequency and severity (Akil et al., 2018). Even though major depressive disorder is diagnosed as a single entity, it is a really heterogeneous disorder characterized by patients having widely varied symptoms, with little to even no overlap of symptomatologies in some cases (Akil et al., 2018). This heterogeneity of depression hinders both research and treatment of this highly prevalent disorder (Fried, 2017). Antidepressants available on the market today were developed based on a theory called monoamine hypothesis of depression, which was established on several key observations made in 1950s. The hypothesis states that the underlying biological reason for depression is depletion of dopamine, serotonin, and/or norepinephrine levels in the central nervous system. It has been demonstrated that increasing the levels of the aforementioned monoamine neurotransmitters in the brain, either by blockage of their reuptake or inhibition of their degradation, alleviates the depression symptoms in patients (Delgado, 2000; Hirschfeld, 2000). Despite the relative effectiveness of currently available antidepressant medications, they are still lacking and possess a variety of drawbacks. Less than half of the patients achieve full remission after the first treatment with antidepressants (Rush, 2007). That leads to trial-and-error approach, where multiple trials of different treatment are needed until the patient is matched with optimal medication. Even then, for patients that do respond to treatment, it takes weeks or months until the depressive symptoms are alleviated (Berton and Nestler, 2006). Some patients also exhibit resistance to antidepressants, which can develop spontaneously in patients previously responsive to treatment or as a result of worsening illness over the course of time (Thase and Schwartz, 2015). Moreover, treatment with antidepressants has numerous side effects, such as fatigue, sleep disturbances, weight and appetite, and sexual dysfunction (Fergusson, 2001). Therefore, there is still an unmet need for more effective, faster, and safer treatment for major depressive disorder. A different approach to depression treatment would be to conceptualize this disease as a circuit dysfunction instead of a neurotransmitter dysfunction. It is possible that the heterogene...

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Mechanosensory neurons in the mouth provide essential information to guide feeding and speech. How classes of oral mechanoreceptors contribute to oral behaviors is not well understood; in particular, the functional properties of lingual mechanoreceptors remain elusive. Previous work identified putative mechanosensory endings in the tongue with novel morphologies; how these fit into current knowledge of mechanosensory neuron classification is not known. To identify functional classes of lingual mechanosensory neurons, we used in vivo calcium imaging of trigeminal ganglia. We first investigated calcium responses of tongue-innervating trigeminal neurons to thermal and mechanical stimulation (e.g., pressure, fluid flow, temperature changes). We found that around 17% of neurons responded to pressure, and that these pressure responders were significantly larger than neurons that only responded to temperature changes. To further investigate the cadre of functionally distinct mechanosensory neurons, we tested responses to brushing and sustained pressures and found that brush-sensitive neurons comprise the majority of tongue-innervating mechanosensory trigeminal neurons. Qualitatively, mechanosensory neurons responded to pressure with distinct kinetics, suggesting the presence of multiple classes of mechanoreceptors. To determine the number of classes, we developed an unbiased multi-layer hierarchical clustering approach to classify calcium response characteristics to pressure stimulation. This approach revealed that mechanosensory neurons displayed five distinct stimulus-response profiles to pressure. Classes include neuronal populations with sustained, transient, high-threshold, and negative responses to force as well as neurons that responded only to brushing. Analysis of cluster representation in transgenic animals with only subsets of labeled neurons reveals molecular markers of clusters and end organ structures. These studies are amongst the first to determine the functional properties of low-threshold mechanosensory neurons innervating the mouse tongue.